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August 18, 2014

In an Ecosystem Within Us, Microbes Evolved to Sway Food Choices

It sounds like science fiction, but it seems that bacteria within us – which outnumber our own cells about 100-fold – may very well be affecting both our cravings and moods to get us to eat what they want, and often are driving us toward obesity.

In an article published this week in the journal BioEssays, researchers from UC San Francisco, Arizona State University and University of New Mexico concluded from a review of the recent scientific literature that microbes influence human eating behavior and dietary choices to favor consumption of the particular nutrients they grow best on, rather than simply passively living off whatever nutrients we choose to send their way.

A Power Struggle Inside the Gut

Bacterial species vary in the nutrients they need. Some prefer fat, and others sugar, for instance. But they not only vie with each other for food and to retain a niche within their ecosystem – our digestive tracts – they also often have different aims than we do when it comes to our own actions, according to senior author Athena Aktipis, PhD, co-founder of the Center for Evolution and Cancer with the Helen Diller Family Comprehensive Cancer Center at UCSF.

Are we at the mercy of our gut bacteria? The above image illustrates how microbes can "pull our strings," driving us to crave foods that give them the nutrients they need, including fat and sugar.

While it is unclear exactly how this occurs, the authors believe this diverse community of microbes, collectively known as the gut microbiome, may influence our decisions by releasing signaling molecules into our gut. Because the gut is linked to the immune system, the endocrine system and the nervous system, those signals could influence our physiologic and behavioral responses.

“Bacteria within the gut are manipulative,” said Carlo Maley, PhD, director of the UCSF Center for Evolution and Cancer and corresponding author on the paper. “There is a diversity of interests represented in the microbiome, some aligned with our own dietary goals, and others not.”

Fortunately, it’s a two-way street. We can influence the compatibility of these microscopic, single-celled houseguests by deliberating altering what we ingest, Maley said, with measurable changes in the microbiome within 24 hours of diet change.

“Our diets have a huge impact on microbial populations in the gut,” Maley said. “It’s a whole ecosystem, and it’s evolving on the time scale of minutes.”

There are even specialized bacteria that digest seaweed, found in humans in Japan, where seaweed is popular in the diet.

The Connection Between Digestive Tract and Brain

Research suggests that gut bacteria may be affecting our eating decisions in part by acting through the vagus nerve, which connects 100 million nerve cells from the digestive tract to the base of the brain.

Athena Aktipis, PhD

Carlo Maley, PhD

“Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve, changing taste receptors, producing toxins to make us feel bad, and releasing chemical rewards to make us feel good,” said Aktipis, who is currently in the Arizona State University Department of Psychology.

In mice, certain strains of bacteria increase anxious behavior. In humans, one clinical trial found that drinking a probiotic containing Lactobacillus casei improved mood in those who were feeling the lowest.

Maley, Aktipis and first author Joe Alcock, MD, from the Department of Emergency Medicine at the University of New Mexico, proposed further research to test the sway microbes hold over us. For example, would transplantation into the gut of the bacteria requiring a nutrient from seaweed lead the human host to eat more seaweed?

The speed with which the microbiome can change may be encouraging to those who seek to improve health by altering microbial populations. This may be accomplished through food and supplement choices, by ingesting specific bacterial species in the form of probiotics, or by killing targeted species with antibiotics. Optimizing the balance of power among bacterial species in our gut might allow us to lead less obese and healthier lives, according to the authors.

Implications for Obesity, Diabetes and even Cancer

The authors met and first discussed the ideas in the BioEssays paper at a summer school conference on evolutionary medicine two years ago.

Aktipis, who is an evolutionary biologist and a psychologist, was drawn to the opportunity to investigate the complex interaction of the different fitness interests of microbes and their hosts and how those play out in our daily lives. Maley, a computer scientist and evolutionary biologist, had established a career studying how tumor cells arise from normal cells and evolve over time through natural selection within the body as cancer progresses.

In fact, the evolution of tumors and of bacterial communities are linked, points out Aktipis, who said some of the bacteria that normally live within us cause stomach cancer and perhaps other cancers.

“Targeting the microbiome could open up possibilities for preventing a variety of disease from obesity and diabetes to cancers of the gastro-intestinal tract. We are only beginning to scratch the surface of the importance of the microbiome for human health,” she said.

The co-authors’ BioEssays study was funded by the National Institutes of Health, the American Cancer Society, the Bonnie D. Addario Lung Cancer Foundation and the Institute for Advanced Study, in Berlin.

UC San Francisco (UCSF), now celebrating the 150th anniversary of its founding, is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco.

Remains of an ancient forest fire preserved in stone

As far back as the time of the dinosaurs, 66 million years ago, forests recovered from fires in the same manner they do today, according to a team of researchers from McGill University and the Royal Saskatchewan Museum.

During an expedition in southern Saskatchewan, Canada, the team discovered the first fossil-record evidence of forest fire ecology - the regrowth of plants after a fire - revealing a snapshot of the ecology on earth just before the mass extinction of the dinosaurs. The researchers also found evidence that the region's climate was much warmer and wetter than it is today.

"Excavating plant fossils preserved in rocks deposited during the last days of the dinosaurs, we found some preserved with abundant fossilized charcoal and others without it. From this, we were able to reconstruct what the Cretaceous forests looked like with and without fire disturbance", says Hans Larsson, Canada Research Chair in Macroevolution at McGill University.

The researchers' discovery revealed that at the forest fire site, the plants are dominated by flora quite similar to the kind that begin forest recovery after a fire today. Ancient forests recovered much like current ones, with plants like alder, birch, and sassafras present in early stages, and sequoia and ginkgo present in mature forests.

"We were looking at the direct result of a 66-million-year old forest fire, preserved in stone," says Emily Bamforth, of the Royal Saskatchewan Museum and the study's first author. "Moreover, we now have evidence that the mean annual temperature in southern Saskatchewan was 10-12 degrees Celsius warmer than today, with almost six times as much precipitation".

"The abundant plant fossils also allowed us for the first time to estimate climate conditions for the closing period of the dinosaurs in southwestern Canada, and provides one more clue to reveal what the ecology was like just before they went extinct", says Larsson, who is also an Associate Professor at the Redpath Museum.

Forest fires can affect both plant and animal biodiversity. The team's finding of ancient ecological recovery from a forest fire will help broaden scientists' understanding of biodiversity immediately before the mass extinction of dinosaurs. "We won't be able to fully understand the extinction dynamics until we understand what normal ecological processes were going on in the background". says Larsson.

A new study reconstructing the evolutionary tree of flu viruses challenges conventional wisdom and solves some of the mysteries surrounding flu outbreaks of historical significance.

The study, published in the journal Nature, provides the most comprehensive analysis to date of the evolutionary relationships of influenza virus across different host species over time. In addition to dissecting how the virus evolves at different rates in different host species, the study challenges several tenets of conventional wisdom, for example the notion that the virus moves largely unidirectionally from wild birds to domestic birds rather than with spillover in the other direction. It also helps resolve the origin of the virus that caused the unprecedentedly severe influenza pandemic of 1918.

The new research is likely to change how scientists and health experts look at the history of influenza virus, how it has changed genetically over time and how it has jumped between different host species. The findings may have implications ranging from the assessment of health risks for populations to developing vaccines.

"We now have a really clear family tree of theses viruses in all those hosts – including birds, humans, horses, pigs – and once you have that, it changes the picture of how this virus evolved," said Michael Worobey, a professor of ecology and evolutionary biology at the University of Arizona, who co-led the study with Andrew Rambaut, a professor at the Institute of Evolutionary Biology at the University of Edinburgh. "The approach we developed works much better at resolving the true evolution and history than anything that has previously been used."

Worobey explained that "if you don't account for the fact that the virus evolves at a different rates in each host species, you can get nonsense – nonsensical results about when and from where pandemic viruses emerged."

"Once you resolve the evolutionary trees for these viruses correctly, everything snaps into place and makes much more sense," Worobey said, adding that the study originated at his kitchen table.

"I had a bunch of those evolutionary trees printed out on paper in front of me and started measuring the lengths of the branches with my daughter's plastic ruler that happened to be on the table. Just like branches on a real tree, you can see that the branches on the evolutionary tree grow at different rates in humans versus horses versus birds. And I had a glimmer of an idea that this would be important for our public health inferences about where these viruses come from and how they evolve."

"My longtime collaborator Andrew Rambaut implemented in the computer what I had been doing with a plastic ruler. We developed software that allows the clock to tick at different rates in different host species. Once we had that, it produces these very clear and clean results."

The team analyzed a dataset with more than 80,000 gene sequences representing the global diversity of the influenza A virus and analyzed them with their newly developed approach. The influenza A virus is subdivided into 17 so-called HA subtypes – H1 through H17 – and 10 subtypes of NA, N1-N10. These mix and match, for example H1N1, H7N9, with the greatest diversity seen in birds.

Using the new family tree of the flu virus as a map showed which species moved to which host species and when. It revealed that for several of its 8 genomic segments avian influenza virus is not nearly as ancient as often assumed.

"What we're finding is that the avian virus has an extremely shallow history in most genes, not much older than the invention of the telephone," Worobey explained.

The research team, which included UA graduate student Guan-Zhu Han and Andrew Rambaut, a professor from the University of Edinburgh who is also affiliated with the U.S. National Institutes of Health, found a strong signature in the data suggesting that something revolutionary happened to avian influenza virus, with the majority of its genetic diversity being replaced by some new variant in a selective sweep in an extremely synchronous event.

Worobey said the timing is provocative because of the correlation of that sudden shift in the flu virus' evolution with historical events in the late nineteenth century.

"In the 1870s, an immense horse flu outbreak swept across North America," Worobey said, "City by city and town by town, horses got sick and perhaps five percent of them died. Half of Boston burned down during the outbreak, because there were no horses to pull the pump wagons. Out here in the West, the U.S. Cavalry was fighting the Apaches on foot because all the horses were sick. This happened at a time when horsepower was actual horse power. The horse flu outbreak pulled the rug out from under the economy."

According to Worobey, the newly generated evolutionary trees show a global replacement of the genes in the avian flu virus coinciding closely with the horse flu outbreak, which the analyses also reveal to be the closest relative to the avian virus.

"Interestingly, a previous research paper analyzing old newspaper records reported that in the days following the horse flu outbreak, there were repeated outbreaks described at the time as influenza killing chickens and other domestic birds," Worobey said. "That's another unexpected link in the history, and the there is a possibility that the two might be connected, given what we see in our trees."

He added that the evolutionary results didn't allow for a definitive determination of whether the virus jumped from horses to birds or vice versa, but a close relationship between the two virus species is clearly there.

With regard to humans, the research sheds light on a longstanding mystery. Ever since the influenza pandemic of 1918, it has not been possible to narrow down even to a hemisphere the geographic origins of any of the genes of the pandemic virus.

"Our study changes that," Worobey said. "It is now clear that most of its genome jumped from birds very close to 1918 in the Western Hemisphere, and there is a suggestion that it was North America in particular."

The results also challenge the accepted wisdom of wild birds as the major reservoir harboring the flu virus, from where it jumps to domestic birds and other species, including humans. Instead, the genetic diversity across the whole avian virus gene pool in domestic and wild birds often appears to trace back to earlier outbreaks of the virus in domestic birds, Worobey explained.

"People tend to think of wild birds as the source of everything, but we see a very strong indication of spillover from domestic birds to wild birds," he said. "It turns out the animals we keep for food and eggs may be substantially shaping the diversity of these viruses in the wild over time spans of decades. That is a surprise."

February 05, 2014

Study gives new insight into similarity of complex brain networks in monkeys, humans

Monkeys that ate a diet rich in omega-3 fatty acids had brains with highly connected and well organized neural networks — in some ways akin to the neural networks in healthy humans — while monkeys that ate a diet deficient in the fatty acids had much more limited brain networking, according to an Oregon Health & Science University study.

The study, published today in the Journal of Neuroscience, provides further evidence for the importance of omega-3 fatty acids in healthy brain development. It also represents the first time scientists have been able to use functional brain imaging in live animals to see the large-scale interaction of multiple brain networks in a monkey. These patterns are remarkably similar to the networks found in humans using the same imaging techniques.

"The data shows the benefits in how the monkeys' brains organize over their lifetime if in the setting of a diet high in omega-3 fatty acids," said Damien Fair, PA-C, Ph.D., assistant professor of behavioral neuroscience and assistant professor of psychiatry in the OHSU School of Medicine and senior author on the paper. "The data also shows in detail how similar the networks in a monkey brain are to networks in a human brain, but only in the context of a diet rich in omega-3-fatty acids."

Omega-3 fatty acids are considered essential fatty acids for the human body. But while they are needed for human health, the body can't make them — it has to get them through food.

The study measured a kind of omega-3 fatty acid called docosahexaenoic acid, or DHA, which is a primary component of the human brain and important in development of the brain and vision. DHA is especially found in fatty fish and oils from those fish — including salmon, mackerel and tuna. Research by a co-author on the paper, Martha Neuringer, Ph.D., an associate scientist in the Division of Neuroscience at OHSU’s Oregon National Primate Research Center, previously showed the importance of DHA for infants’ visual development — a finding that led to the addition of DHA to infant formulas.

The scientists studied a group of older rhesus macaque monkeys — 17 to 19 years of age — from ONPRC that had been fed all of their lives either a diet low or high in omega-3 fatty acids, including DHA. The study found that the monkeys that had the high-DHA diet had strong connectivity of early visual pathways in their brains. It also found that monkeys with the high-DHA diet showed greater connections within various brain networks similar to the human brain — including networks for higher-level processing and cognition, said David Grayson, a former research assistant in Fair's lab and first author on the paper. Grayson is now studying at the Center for Neuroscience, University of California-Davis.

"For example, we could see activity and connections within areas of the macaque brain that are important in the human brain for attention," said Fair.

Now that those measurements and monitoring are possible, Fair said, the next step will be to analyze whether the monkeys with deficits in certain networks have behavioral patterns that are similar to behavioral patterns in humans with certain neurological or psychiatric conditions — including Attention Deficit Hyperactivity Disorder and autism.

Fair, who was among the 102 people given the 2013 Presidential Early Career Award for Scientists and Engineers by President Barack Obama, is a leader in using the same kind of brain imaging to explore brain networks in children with ADHD and autism. He said he hopes to use these non-invasive brain imaging techniques to provide an important link between research in humans and animals in order to better characterize, treat, and prevent these types of developmental mental health issues.

Fair added that another longer-term goal would be to study brain development in the monkeys fed various diets from birth into maturity.

"It would be important to see how a diet high in omega-3s might affect brain development early on in their lives, and across their lifespan," Fair said.

The study was funded by the Oregon Clinical and Translational Research Institute (through National Institutes of Health grant UL1TR000128), several other NIH grants (grants UL1 RR024140, P510D011092, K99/R00 MH091238, R01 MH096773, EY13199, and DK29930) and the Foundation Fighting Blindness.

About OHSU Brain Institute

The Oregon Health & Science University Brain Institute is a national neuroscience leader in patient care, research and education. With more than 1,000 brain scientists and specialists, OHSU is home to one of the largest communities of brain and central nervous system experts in the nation. OHSU Brain Institute scientists have won national recognition for breaking new ground in understanding Alzheimer’s disease and for discoveries that have led to new treatments for Parkinson’s disease, multiple sclerosis, stroke and other brain disorders and diseases.

About OHSU

Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.

Byline: Dianna Padilla, State University of New York at Stony Brook Billie J. Swalla, University of Washington Brian Tsukimura, California State University at Fresno

Newswise — Why can some animals respond to climate change, while others cannot? How do animals develop properly when conditions change? How do animals respond quickly or build new neural pathways but maintain past abilities and function? These questions have perplexed biologists for decades. The challenge in addressing these questions is that biological systems are complex, and they operate at many different spatial scales and time scales simultaneously. Thus, the conventional tools of biologists limit the advances that can be made. New approaches are needed to make progress in answering these important questions for animal biology.

What new insights might be gleaned when engineers and mathematicians work with biologists to answer these fundamental questions? A special symposium at the 2014 Society for Integrative and Comparative Biology annual conference brings together biologists, mathematicians and engineers, who will investigate the potential and power of a new, quantitative organismal systems biology to address these questions.

Speakers include a mix of biologists from different fields, including physiology, neural biology, development, genetics, functional morphology, and ecological and evolutionary biology. They join with mathematicians and engineers and will present work that illustrates the potential power of cross-disciplinary approaches for answering these complex questions. The speakers will also explore how organismal biology can be used to help solve questions that have daunted mathematicians and engineers. Talks will include a wide range of questions from locomotion, physiology, development, networks, and ecology, from the level of genomics to whole organism responses to change. Talks in this symposium will illustrate the power of engineering and quantitative approaches to address and test complex questions, and lead us to a new organismal systems biology.

The symposium will be held Sunday, January 5. Ten speakers will present examples of research and modeling that illustrates how new approaches can help us investigate important questions about complex biological systems, as well as the big questions that remain to be tackled. Immediately following the symposium, complementary posters will be presented. On Monday, January 6 there will be a session of additional complementary papers.

January 05, 2014

They’re just like those in your nose, but instead of conjuring up a cup of coffee, they might make you cough

January 2, 2014

Article Body 2010

Your nose is not the only organ in your body that can sense cigarette smoke wafting through the air. Scientists at Washington University in St. Louis and the University of Iowa have shown that your lungs have odor receptors as well.

Unlike the receptors in your nose, which are located in the membranes of nerve cells, the ones in your lungs are in the membranes of neuroendocrine cells. Instead of sending nerve impulses to your brain that allow it to “perceive” the acrid smell of a burning cigarette somewhere in the vicinity, they trigger the flask-shaped neuroendocrine cells to dump hormones that make your airways constrict.

The newly discovered class of cells expressing olfactory receptors in human airways, called pulmonary neuroendocrine cells, or PNECs, were found by a team led by Yehuda Ben-Shahar, PhD, assistant professor of biology, in Arts & Sciences, and of medicine at Washington University in St. Louis, and including colleagues Steven L. Brody, MD, and Michael J. Holtzman, MD, of the Washington University School of Medicine, and Michel J. Welsh, MD, of the University of Iowa Carver College of Medicine.

“We forget,” said Ben-Shahar, “that our body plan is a tube within a tube, so our lungs and our gut are open to the external environment. Although they’re inside us, they’re actually part of our external layer. So they constantly suffer environmental insults,” he said, “and it makes sense that we evolved mechanisms to protect ourselves.”

In other words, the PNECs, described in the March issue of the American Journal of Respiratory Cell and Molecular Biology, are sentinels, guards whose job it is to exclude irritating or toxic chemicals.

The cells might be responsible for the chemical hypersensitivity that characterizes respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Patients with these diseases are told to avoid traffic fumes, pungent odors, perfumes and similar irritants, which can trigger airway constriction and breathing difficulties.

The odor receptors on the cells might be a therapeutic target, Ben-Shahar suggests. By blocking them, it might be possible to prevent some attacks, allowing people to cut down on the use of steroids or bronchodilators.

Every breath you take When a mammal inhales, volatile chemicals flow over two patches of specialized epithelial tissue high up in the nasal passages. These patches are rich in nerve cells with specialized odorant-binding molecules embedded in their membranes.

If a chemical docks on one of these receptors, the neuron fires, sending impulses along the olfactory nerve to the olfactory bulb in the brain, where the signal is integrated with those from hundreds of other similar cells to conjure the scent of old leather or dried lavender.

Aware that airway diseases are characterized by hypersensitivity to volatile stimuli, Ben-Shahar and his colleagues realized that the lungs, like the nose, must have some means of detecting inhaled chemicals.

Earlier, a team at the University of Iowa, where Ben-Shahar was a postdoctoral research associate, had searched for genes expressed by patches of tissue from lung transplant donors. They found a group of ciliated cells that express bitter taste receptors. When offending substances were detected, the cilia beat more strongly to sweep them out of the airway. This result was featured on the cover of the Aug. 28, 2009, issue of Science.

But since people are sensitive to many inhaled substances, not just bitter ones, Ben-Shahar decided to look again. This time he found that these tissues also express odor receptors, not on ciliated cells but instead on neuroendocrine cells, flask-shaped cells that dump serotonin and various neuropeptides when they are stimulated.

Ben-Shahar

“They’re beautiful cells,” said Ben-Shahar, of the pulmonary neuroendocrine cells he has been studying in lung tissues. The flask-like cells that are full of serotonin (stained green here) and other chemicals extend processes up through the epithelial cells (purple) lining the airways to monitor the chemical makeup of each breath. The top part of the image is a plan view of the airway lining and the bottom part is a section through the lining.

This made sense. “When people with airway disease have pathological responses to odors, they’re usually pretty fast and violent,” said Ben-Shahar. “Patients suddenly shut down and can’t breathe, and these cells may explain why.”

Ben-Shahar stresses the differences between chemosensation in the nose and in the lung. The cells in the nose are neurons, he points out, each with a narrowly tuned receptor, and their signals must be woven together in the brain to interpret our odor environment.

The cells in the airways are secretory, not neuronal, cells, and they may carry more than one receptor, so they are broadly tuned. Instead of sending nerve impulses to the brain, they flood local nerves and muscles with serotonin and neuropeptides. “They are possibly designed,” he said, “to elicit a rapid, physiological response if you inhale something that is bad for you.”

Ben-Shahar

A diagram of the airway lining suggests how the pulmonary neuroendocrine cells (red) trigger a response to inhaled chemicals. When a chemical (orange triangle) docks on a receptor (black) they dump secretory chemicals (thin orange arrows), which have an immediate but localized effect on muscles (blue) and nerves (pink), possibly triggering responses such as a cough.

The different mechanisms explain why cognition plays a much stronger role in taste and smell than in coughing in response to an irritant. It is possible, for example, to develop a taste for beer. But nobody learns not to cough; the response is rapid and largely automatic.

The scientists suspect these pulmonary neuroscretory cells contribute to the hypersensitivity of patients with COPD to airborne irritants. COPD is a group of diseases, including emphysema, that is characterized by coughing, wheezing, shortness of breath and chest tightness.

When the scientists looked at the airway tissues from patients with COPD, they discovered that they had more of these neurosecretory cells than airway tissues from healthy donors.

Of mice and men As a geneticist, Ben-Shahar would like to go farther, knocking out genes to make sure that the derangement of neurosecretory cells isn’t just correlated with airway diseases but instead suffices to produce it.

But there is a problem. “For example, a liver from a mouse and a liver from a human are pretty similar, they express the same types of cells. But the lungs from different mammalian species are often very different; you can see it at a glance,” Ben-Shahar said.

This makes it challenging to unravel the biomolecular mechanisms of respiratory diseases.

Still, he is hopeful that the PNEC pathways will provide targets for drugs that would better control asthma, COPD and other respiratory diseases. They would be welcome. There has been a steep rise in these diseases in the past few decades, treatment options have been limited, and there are no cures.

They’re just like those in your nose, but instead of conjuring up a cup of coffee, they might make you cough

January 2, 2014

Article Body 2010

Your nose is not the only organ in your body that can sense cigarette smoke wafting through the air. Scientists at Washington University in St. Louis and the University of Iowa have shown that your lungs have odor receptors as well.

Unlike the receptors in your nose, which are located in the membranes of nerve cells, the ones in your lungs are in the membranes of neuroendocrine cells. Instead of sending nerve impulses to your brain that allow it to “perceive” the acrid smell of a burning cigarette somewhere in the vicinity, they trigger the flask-shaped neuroendocrine cells to dump hormones that make your airways constrict.

The newly discovered class of cells expressing olfactory receptors in human airways, called pulmonary neuroendocrine cells, or PNECs, were found by a team led by Yehuda Ben-Shahar, PhD, assistant professor of biology, in Arts & Sciences, and of medicine at Washington University in St. Louis, and including colleagues Steven L. Brody, MD, and Michael J. Holtzman, MD, of the Washington University School of Medicine, and Michel J. Welsh, MD, of the University of Iowa Carver College of Medicine.

“We forget,” said Ben-Shahar, “that our body plan is a tube within a tube, so our lungs and our gut are open to the external environment. Although they’re inside us, they’re actually part of our external layer. So they constantly suffer environmental insults,” he said, “and it makes sense that we evolved mechanisms to protect ourselves.”

In other words, the PNECs, described in the March issue of the American Journal of Respiratory Cell and Molecular Biology, are sentinels, guards whose job it is to exclude irritating or toxic chemicals.

The cells might be responsible for the chemical hypersensitivity that characterizes respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Patients with these diseases are told to avoid traffic fumes, pungent odors, perfumes and similar irritants, which can trigger airway constriction and breathing difficulties.

The odor receptors on the cells might be a therapeutic target, Ben-Shahar suggests. By blocking them, it might be possible to prevent some attacks, allowing people to cut down on the use of steroids or bronchodilators.

Every breath you take When a mammal inhales, volatile chemicals flow over two patches of specialized epithelial tissue high up in the nasal passages. These patches are rich in nerve cells with specialized odorant-binding molecules embedded in their membranes.

If a chemical docks on one of these receptors, the neuron fires, sending impulses along the olfactory nerve to the olfactory bulb in the brain, where the signal is integrated with those from hundreds of other similar cells to conjure the scent of old leather or dried lavender.

Aware that airway diseases are characterized by hypersensitivity to volatile stimuli, Ben-Shahar and his colleagues realized that the lungs, like the nose, must have some means of detecting inhaled chemicals.

Earlier, a team at the University of Iowa, where Ben-Shahar was a postdoctoral research associate, had searched for genes expressed by patches of tissue from lung transplant donors. They found a group of ciliated cells that express bitter taste receptors. When offending substances were detected, the cilia beat more strongly to sweep them out of the airway. This result was featured on the cover of the Aug. 28, 2009, issue of Science.

But since people are sensitive to many inhaled substances, not just bitter ones, Ben-Shahar decided to look again. This time he found that these tissues also express odor receptors, not on ciliated cells but instead on neuroendocrine cells, flask-shaped cells that dump serotonin and various neuropeptides when they are stimulated.

Ben-Shahar

“They’re beautiful cells,” said Ben-Shahar, of the pulmonary neuroendocrine cells he has been studying in lung tissues. The flask-like cells that are full of serotonin (stained green here) and other chemicals extend processes up through the epithelial cells (purple) lining the airways to monitor the chemical makeup of each breath. The top part of the image is a plan view of the airway lining and the bottom part is a section through the lining.

This made sense. “When people with airway disease have pathological responses to odors, they’re usually pretty fast and violent,” said Ben-Shahar. “Patients suddenly shut down and can’t breathe, and these cells may explain why.”

Ben-Shahar stresses the differences between chemosensation in the nose and in the lung. The cells in the nose are neurons, he points out, each with a narrowly tuned receptor, and their signals must be woven together in the brain to interpret our odor environment.

The cells in the airways are secretory, not neuronal, cells, and they may carry more than one receptor, so they are broadly tuned. Instead of sending nerve impulses to the brain, they flood local nerves and muscles with serotonin and neuropeptides. “They are possibly designed,” he said, “to elicit a rapid, physiological response if you inhale something that is bad for you.”

Ben-Shahar

A diagram of the airway lining suggests how the pulmonary neuroendocrine cells (red) trigger a response to inhaled chemicals. When a chemical (orange triangle) docks on a receptor (black) they dump secretory chemicals (thin orange arrows), which have an immediate but localized effect on muscles (blue) and nerves (pink), possibly triggering responses such as a cough.

The different mechanisms explain why cognition plays a much stronger role in taste and smell than in coughing in response to an irritant. It is possible, for example, to develop a taste for beer. But nobody learns not to cough; the response is rapid and largely automatic.

The scientists suspect these pulmonary neuroscretory cells contribute to the hypersensitivity of patients with COPD to airborne irritants. COPD is a group of diseases, including emphysema, that is characterized by coughing, wheezing, shortness of breath and chest tightness.

When the scientists looked at the airway tissues from patients with COPD, they discovered that they had more of these neurosecretory cells than airway tissues from healthy donors.

Of mice and men As a geneticist, Ben-Shahar would like to go farther, knocking out genes to make sure that the derangement of neurosecretory cells isn’t just correlated with airway diseases but instead suffices to produce it.

But there is a problem. “For example, a liver from a mouse and a liver from a human are pretty similar, they express the same types of cells. But the lungs from different mammalian species are often very different; you can see it at a glance,” Ben-Shahar said.

This makes it challenging to unravel the biomolecular mechanisms of respiratory diseases.

Still, he is hopeful that the PNEC pathways will provide targets for drugs that would better control asthma, COPD and other respiratory diseases. They would be welcome. There has been a steep rise in these diseases in the past few decades, treatment options have been limited, and there are no cures.

October 07, 2013

The unique genomic signature could serve as a research model for founding events

Researchers at the Sainte-Justine University Hospital Center and University of Montreal have discovered that the genomic signature inherited by today's 6 million French Canadians from the first 8,500 French settlers who colonized New France some 400 years ago has gone through an unparalleled change in human history, in a remarkably short timescale. This unique signature could serve as an ideal model to study the effect of demographic processes on human genetic diversity, including the identification of possibly damaging mutations associated with population-specific diseases.

Until now, changes in the relative proportion of rare mutations, that could be both detrimental and adaptive, had only been shown over relatively long timescales, by comparing African and European populations. According to Dr. Alan Hodgkinson, the co-first author of an article published online in PLOS Genetics recently and a postdoctoral fellow, "through this first in-depth genomic analysis of more than a hundred French Canadians, we have been surprised to find that in less than 20 generations, the distribution and relative proportion of rare, potentially damaging variants have changed more than we anticipated."

Such an increase in rare variation is presumably due to a high birth rate of the settlers and the genetic isolation from France, with limited exchange with other non-French communities in the same geographical area, since emigration virtually stopped after 1759, just before the English conquest. Indeed, the founding population is estimated to have contributed 90% of the current French Canadian genetic pool.

According to Dr. Philip Awadalla, senior author and principal investigator, "the fact that two very close populations (French versus French Canadians) accumulate such an excess of differences in rare variants has important consequences in the design of genetic studies, including the identification of possibly damaging mutations associated with diseases specific to this population." The model unveiled by the researchers could also serve conservation genetics, namely in determining the impact of genetic diversity on the minimal number of individuals required for the survival of specific species or captive populations.

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About the study

This first whole-exome sequencing study of the French Canadian population was performed at the Child Health Genomics Platform of the Sainte-Justine University Hospital Research Center andGenome Quebec - McGill University Innovation Center. The results were published on line in PLOS Genetics on September 26, 2013, under the title "Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans" The study benefited from the financial support of Genome Québec, Canadian Foundation for Innovation, and the Canadian Institute of Health Research.

September 30, 2013

Rensselaer Researchers Propose New Theory To Explain Seeds of Life in Asteroids

September 30, 2013

A new look at the early solar system introduces an alternative to a long-taught, but largely discredited, theory that seeks to explain how biomolecules were once able to form inside of asteroids. In place of the outdated theory, researchers at Rensselaer Polytechnic Institute propose a new theory — based on a richer, more accurate image of magnetic fields and solar winds in the early solar system, and a mechanism known as multi-fluid magneto-hydrodynamics — to explain the ancient heating of the asteroid belt.

Although today the asteroid belt between Mars and Jupiter is cold and dry, scientists have long known that warm, wet conditions, suitable to formation of some biomolecules, the building blocks of life, once prevailed. Traces of bio-molecules found inside meteorites – which originated in the asteroid belt –could only have formed in the presence of warmth and moisture. One theory of the origin of life proposes that some of the biomolecules that formed on asteroids may have reached the surfaces of planets, and contributed to the origin of life as we know it.

“The early sun was actually dimmer than the sun today, so in terms of sunlight, the asteroid belt would have been even colder than it is now. And yet we know that some asteroids were heated to the temperature of liquid water, the ‘goldilocks zone,’ which enabled some of these interesting biomolecules to form,” said Wayne Roberge, a professor of physics within the School of Science at Rensselaer, and member of the New York Center for Astrobiology, who co-authored a paper on the subject with Ray Menzel, a graduate student in physics. “Here’s the question: How could that have happened? How could that environment have existed inside an asteroid?”

In the paper, titled “Reexamination of Induction Heating of Primitive Bodies in Protoplanetary Disks” and published today in The Astrophysical Journal, Menzel and Roberge revisit and refute one of two theories proposed decades ago to explain how asteroids could have been heated in the early solar system. Both of the established theories — one involving the same radioactive process that heats the interior of Earth, and the other involving the interaction of plasma (super-heated gases that behave somewhat like fluids) and a magnetic field — are still taught to students of astrobiology. Although radioactive heating of asteroids was undoubtedly important, current models of radioactive heating make some predictions about temperatures in the asteroid belt that are inconsistent with observations.

Motivated by this, Roberge and Menzel reviewed the second of the two theories, which is based on an early assessment of the young sun and the premise that an object moving through a magnetic field will experience an electric field. According to this theory, as an asteroid moves through the magnetic field of the solar system, it will experience an electric field, which will in turn push electrical currents through the asteroid, heating the asteroid in the same way that electrical currents heat the wires in a toaster.

“It’s a very clever idea, and the mechanism is viable, but the problem is that they made a subtle error in how it should be applied, and that’s what we correct in this paper,” said Roberge. “In our work, we correct the physics, and also apply it to a more modern understanding of the young solar system.”

Menzel said the researchers have now definitively refuted the established theory.

“The mechanism requires some extreme assumptions about the young solar system,” Menzel said. “They assumed some things about what the young sun was doing which are just not believed to be true today. For example, the young sun would have had to produce a powerful solar wind which blew past the asteroids, and that’s just no longer believed to be true.”

The solar wind, and the plasma stream it produced, was not as powerful as early theorists assumed, and the researchers have corrected those calculations based on the current understanding of the young sun. Roberge said the early theorists also incorrectly calculated the position of the electric field asteroids would have experienced. Roberge said that, in reality, an electric field would have permeated the asteroid and the space around it, a mistake very few researchers would have realized.

“We’ve calculated the electric field everywhere, including the interior of the asteroid,” Roberge said. “How that electric field comes about is a very specialized thing; about 10 people in the world study that kind of physics. Fortunately, two of them are here at RPI working together.”

What emerges, Menzel and Roberge said, is a new possibility, based on the corrected understanding of the electric fields the asteroids would have experienced, the solar wind and plasma conditions that would have prevailed, and a mechanism known as multi-fluid magneto-hydrodynamics.

Magneto-hydrodynamics is the study of how charged fluids – including plasmas – interact with magnetic fields. The magnetic fields can influence the motion of the charged fluid, or plasma, and vice versa. Magneto-hydrodynamics had a moment of fame as the propulsion system for an experimental nuclear submarine in the 1990 movie The Hunt for Red October.

Multi-fluid magneto-hydrodynamics are an even more specialized variation of the mechanism that apply in situations where the plasma is very weakly ionized, and the neutral particles behave distinctly from the charged particles.

“The neutral particles interact with the charged particles by friction,” Menzel said. “So this creates a complex problem of treating the dynamics of the neutral gas and allowing for the presence of the small number of charged particles interacting with the magnetic field.”

Menzel and Roberge said their new theory is promising, but it raises many questions that merit further exploration.

“We’re just at the beginning of this. It would be wrong to assert that we’ve solved this problem,” Roberge said. “What we’ve done is to introduce a new idea. But through observations and theoretical work, we know have a pretty good paradigm.”

And much as Menzel and Roberge benefited from recent progress in understanding the physical conditions in an emerging planetary system, they hope their own work will advance the field of astrophysics.

“There are a lot of byproducts of this work because, in the course of doing this, we had to really zero in on how an asteroid interacts with the plasma of the young solar system,” said Roberge. “There are a lot of physical processes that we had to consider that have not been considered in this context before.”

- See more at: http://news.rpi.edu/content/2013/09/30/rensselaer-researchers-propose-new-theory-explain-seeds-life-asteroids#sthash.9CnWWpVj.dpuf

September 23, 2013

[....I wonder if this could explain the aggressive behavior of some nations?--WD]

Genes related to self-control could be 'disabled' by the prenatal environment

Chronic aggressive behaviour exhibited by some boys from disadvantaged families may be due to epigenetic changes during pregnancy and early childhood. This is highlighted by two studies conducted by a team led by Richard E. Tremblay, professor emeritus at the University of Montreal and Moshe Szyf, professor at McGill University, published in the journal PLOS ONE. The first author of the two papers, Nadine Provençal, was jointly supervised by professors Szyf and Tremblay.

Epigenetic changes possibly related to the prenatal environment

In the first study, published in July, the team found that among men who had chronic aggressive behaviour during childhood and adolescence, blood levels of four biomarkers of inflammation were lower than in men who exhibited average levels of aggressive behaviour in their youth, from 6 to 15 years of age. "This means that using four specific biomarkers of inflammation, called cytokines, we were able to distinguish men with chronic physical aggression histories from those without," says Tremblay, a researcher specializing in developmental psychology. In the second study, it was observed in the same men with aggressive pasts, that the DNA encoding the cytokines showed methylation patterns different from those of the comparison group.

"Methylation is an epigenetic modification—hence reversible—of DNA, in relation to parental imprinting. It plays a role in regulating gene expression", says Szyf, who specializes in epigenetics.

The pre- and postnatal environment could cause these differences in biomarkers associated with chronic aggression," Szyf added. Various studies conducted with animals show that hostile environments during pregnancy and early childhood have an impact on gene methylation and gene programming leading to problems with brain development, particularly in regard to the control of aggressive behaviour.

Previous work by Tremblay's team suggest that men with aggressive pasts have one thing in common: the characteristics of their mothers. "They are usually young mothers at the birth of their first child, with low education, often suffering from mental health problems, and with substance use problems," Tremblay explained. The significant difficulties these mothers experienced during pregnancy and the early childhood of their child may have an impact on the expression of genes related to brain development, the immune system, and many other biological systems critical for the development of their child.

A nearly 30-year follow-up

The blood samples used in the studies published this summer in PLOS ONE were collected from 32 participants who took part in either of two longitudinal studies that begun nearly 30 years ago by Tremblay's team. The first study followed young Quebecers from disadvantaged backgrounds, while the second involved a representative sample of children who were in kindergarten in Quebec in 1986-87.

It is important to note that in disadvantaged families, the rate of boys with chronic aggressive behaviour represents about 4% of the population. This greatly restricts the selection of potential participants. "Once they are adults, they are difficult to find because they have disorganized lifestyles," Tremblay said.

A prevention perspective

This difficulty has not stopped him from pursuing his research further. "We are studying the impact of the socioeconomic environment on the third generation, now that these children are grown up and have children," Tremblay noted. No study has yet been published on the subject, he anticipates "significant intergenerational ties, since we observed an association between parental criminality of the first generation and the behaviour of their children."

Nevertheless, the researcher, who has conducted his work for decades with a prevention perspective, is optimistic. "If our results show that behavioural problems originate from as far back as pregnancy, it means that we can reduce violence through preventive intervention from as early as pregnancy," says Tremblay. We have already shown that support given to families of aggressive boys in kindergarten prevents school dropout and crime in adulthood.

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Notes

The University of Montreal is officially known as Université de Montréal. This document is a translation of a text originally written in French by Martin LaSalle, Université de Montréal. This work was supported by a fellowship from the Genes, Environment and Health Training Program from Canadian Institutes of Health Research (CIHR), grants from the Canadian Institutes of Health Research, the Social Sciences Humanities Research Council of Canada, Fonds de recherche du Québec – Santé (FRQ-S) and Fonds de recherche du Québec – Société et culture (FRQ-SC), the Sackler Program in Psychobiology and Epigenetics at McGill University and from the Canadian Institute for Advanced Research.